Alkyl-Substituted Cyclohexenones

Photolysis of 4,4-dimethylcyclohexenone in r-butyl alcohol gives ketones from the type A rearrangement  

In acetic acid these products are accompanied by products (83) and (84). 

Dauben et al. have investigated the scope of the photochemical type A rearrangement/ They conclude that the rearrangement occurs only if the fourth carbon atom of the 2-cyclohexenone ring is fully alkyl-substituted. If this requirement is not met, photodimers are the major products. This substituent requirement is necessary but not sufficient to ensure rearrangement since the presence of other groups can inhibit the reaction. 

Compounds that do not give type A rearrangement are as follows  

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The addition of carbon nucleophiles to complex (27), followed by demetallation, is equivalent to the y-alkylation of cyclohexenone. This overall transformation can also be accomplished directly via addition of electrophiles to dienolsilanes, but it becomes nontrivial for cases where the cyclohexenone C-4 position is already substituted.37 On the other hand, 1 -substituted cyclohexadienyliron complexes, such as (30), react very cleanly with certain carbon nucleophiles, at the substituted dienyl terminus. This provides useful methodology for the construction of 4,4-disubstituted cyclohexenones, and has been employed in a variety of natural product syntheses. 

Substituted cyclohexenones are prepared by the alkylation of 2-cyano-6-methoxytetrahydropyran, a cyclic protected cyanohydrin (Scheme 13). ... 

With a catalytic amount of the palladium complex PdCl2(CH3CN)2 the presence of benzoquinone, anilines 37 react with methyl vinyl ketone or methyl acrylate to afford the enaminones 38 in moderate to good yields, Scheme 11. The reaction is sensitive to the amine substitution for example, benzylamine and A-unsubstituted anilines except o-bromoaniline failed to give the desired enaminones. Alkyl-substituted enones (methyl crotonate, cyclopentenone, cyclohexenone) presumably were sterically inhibited from coordination with the palladium because they also failed to undergo the reaction (81JOC2561). 

The enone mesylate (85), prepared in almost quantitative yield from cyclohexane-1,3-dione, reacts at room temperature with various nucleophiles [e.g. NaOEt, MejNH, PhCH2SNa) to give /3-functionalized cyclohexenones, e.g. (86). Dimedone is also a suitable precursor, but the sequence fails with acyclic 1,3-diones. By contrast, the dilithio species (87), functioning as an equivalent of the /3-vinyl carbanion of cyclohexenone, reacts with electrophiles (e.g. alkyl iodides, aldehydes, ketones) to give /3-substituted cyclohexenones, e.g. (88)." ... 

The acid chlorides of to-(2-thienyl) substituted butyric (122) and valeric acids (123), as well as the corresponding 5-alkyl-2-thienyl-substituted compounds, undergo internal Friedel-Crafts reaction (SnCl4,CS2) at the 3-position in 70-80% yield, to give the corresponding cyclohexenones (124) and cycloheptenones (125). ... 

Professor Shibasaki has also investigated (J. Am. Chem. Soc. 125 15840,2003) Michael addition to prepare alkylated secondary centers in high enantiomeric excess. Addition of substituted acetoacetates to cyclohexenone and to cycloheptenone proceeds with high . With the more reactive cyclopentenone, the is slightly lower. 

Houck and coworkers postulate that the origin of the regioselectivity is at the biradicalforming step and directly affected by the polarity of the alkene. The /J-carbon, considered as nucleophilic, adds rapidly to the less substituted side of the electron-deficient alkene, whereas a position considered as an a-acyl radical (more electrophilic than an alkyl radical) adds rapidly to the less substituted side of electron-rich alkenes. The calculated relative energies for the addition of jtjt triplet acrolein to different substituted alkenes at the first bond-forming step (Table 3) are found to be in good agreement with experimental values determined in the photoaddition of cyclohexenone to the related alkene. 

In view of the selectivity of lithiation of the imine system, to get a -syn deprotonation and subsequently substitution, Fraser investigated the scope of asymmetric induction of a chiral imine, i.e. cyclohexenone imine, that derives from TV-a-phenethylamine 34. On alkylation by Mel or EtI, he obtained a-substituted cyclohexanones in ee of 50%66. Ma-Jacheet and Horeau67 and Yamada and coworkers68, who used this technique, obtained 25-45% ee. Free rotation around the C—N bond, as well as the lack of control of the configuration of the alkylation product, were the reasons ascribed for the low amount of asymmetric induction. A better enantioselectivity was achieved when the imine had an inner ligand (OMe), that makes the lithioenamine 35 more rigid by /w/ramolecular chelation. 

The a./y alkylation ratio of the intramolecular nucleophilic substitution reaction of an a,y9-unsaturated cyclohexenone tosylate can also be controlled by the right choice of solvent. The desired y-alkylation - the final step of the total synthesis of the sesquiterpene yS-vetivone - is favoured by NaOH in CH3SOCH3/H2O, in contrast to (CH3)3C0K/(CH3)3C0H, which promotes a-alkylation [670],... 

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